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Ion channel defects produce a clinically diverse set of disorders that range from cystic fibrosis and some forms of migraine to renal tubular defects and episodic ataxias. This review discusses diseases related to impaired function of the skeletal muscle acetylcholine receptor and calcium channels of the motor nerve terminal. Myasthenia gravis is an autoimmune disease caused by antibodies directed toward the skeletal muscle acetylcholine receptor that compromise neuromuscular transmission. Congenital myasthenias are genetic disorders, a subset of which are caused by mutations of the acetylcholine receptor. Lambert-Eaton myasthenic syndrome is an immune disorder characterized by impaired synaptic vesicle release likely related to a defect of calcium influx. The disorders will illustrate new insights into synaptic transmission and ion channel structure that are relevant for all ion channel disorders.

Myofibrillar Ca sensitivity and single-channel acetylcholine receptor (AChR) currents were studied in garter snake (Thamnophis sirtalis sirtalis) costocutaneous muscle fibers. Nomarski optics were used to identify tonic and fast- and slow-twitch fibers. Measurements of tension generation were made using chemically skinned fibers. The maximum tensions of the three types of fibers were similar, and the fast- and slow-twitch fibers had similar Ca sensitivities. Compared with twitch fibers, tonic fibers had lower threshold Ca concentrations for tension generation and a larger range of Ca concentrations between threshold and maximum tension. The AChR channels were studied by enzymatically removing the nerve terminals and performing patch-clamp recordings on the exposed postsynaptic membrane. Twitch fibers had only one class of end-plate channel with a conductance of approximately 51 pS. Tonic fibers had two types of synaptic channels. One AChR channel in the tonic fibers resembled the type seen in twitch fibers. The other channel in tonic fibers had a smaller conductance of approximately 33 pS and resembled extrajunctional AChRs on denervated twitch fibers.

This article reviews the biophysics of ion passage through membrane pores, as well as the physical factors that control the ion selectivity, gating, and conductance of an ionic channel. Different voltage clamp techniques are discussed in detail. The biophysical properties of sodium channels are reviewed.

Sodium currents were recorded in rat fast and slow twitch muscle fibers. Changes in the membrane potential around the resting potential produced slow changes in the sodium current amplitude due to alterations of the slow inactivation process that was increased by steady depolarization and removed by prolonged hyperpolarization. In contrast, classical fast inactivation was not operative around the resting potential, and depolarizations of greater than 20 mV were required to close half of the channels by fast inactivation. Because slow inactivation is operative around the resting potential of mammalian muscle fibers, it may partially explain why small depolarizations, such as those that occur in some patients with periodic paralysis, can reduce excitability.

This article reviews the different forms of ionic channels: voltage-gated, agonist-gated, and agonist- and second messenger-modified channels. The recent advances in our knowledge of the amino acid sequence of the sodium channel and the nicotinic acetylcholine receptor and the relationship of the primary structure to the channels' quarternary structure and function are discussed.

1. Voltage-clamp Na+ currents (INa) were studied in rat soleus slow-twitch muscle fibres at about 18 degrees C using the loose-patch-clamp technique. The maximum inward current density was produced by depolarizations to about -19 mV. 2. Fast inactivation was studied utilizing 20 ms conditioning potentials. INa was reduced by 50% with conditioning potentials to about -70 mV. 3. Changes in the conditioning membrane potential produced slow changes in the peak INa due to a slow inactivation process. INa was reduced by 50% at about -86 mV due to slow inactivation. 4. The mean maximum inward INa when slow inactivation was fully removed was 6.83 mA cm-2. 5. Due to the slow inactivation process, slow-twitch fibres were less susceptible to reduction in INa than fast-twitch fibres.